Background Infections are one of the major causes of morbidity and mortality in critically ill patients. Severe infections should be treated at earlier stages, but the diagnosis is difficult as the clinical presentation results are unspecific. Recently, the neutrophils Fc gamma receptor, recognized by monoclonal antibodies cluster of differentiation 64 (CD64), has been proposed as an infection marker. The aim of the present study was to evaluate CD64 as a marker of infection in our polyvalent intensive care unit, distinguishing early infection from noninfected inflammation. Methods We evaluated 93 consecutive patients presenting with infection signs on admission. CD64, C-reactive protein (CRP), and white blood cell count were collected. After a test for normal distribution, data were analyzed nonparametrically and reported as median and interquartile range (IQR); then, Kruskal-Wallis and Mann-Whitney tests were performed. Statistically significant difference was defined as P < 0.05. Results C-reactive protein (median, 17.4 mg/L; IQR, 11.4–27.2 mg/L vs median, 10.1 mg/L; IQR, 7.5–13.7mg/L) and CD64 (median, 3842 antibody-binding capacity [ABC]; IQR, 2799–5283 ABC vs median, 768.5 ABC; IQR, 532.3–1269.3 ABC) showed a significant difference between septic and nonseptic patients, respectively. Receiver operating characteristic curves of CD64, CRP, and white blood cell count showed the superiority of CD64: considering a cutoff of 2000 antibody-binding capacity for infection, sensitivity was 90.2% and specificity was 96.9% in comparison with CRP (sensitivity, 85.2%; and specificity, 46.9% for cutoff of 10 mg/L). CD64 expression, but not CRP, was able to differentiate the septic stages (P < 0.001). Conclusions Neutrophil CD64 represents a sensitive and specific marker for the early diagnosis of systemic infections in adult patients admitted to intensive care unit, superior to traditional hematological parameters and CRP.